Current perspectives on high-risk genomic profiles in chronic myeloid leukemia: from bench to clinical practice

Chronic myeloid leukemia (CML) is defined by BCR::ABL1 rearrangement, yet its genomic architecture extends well beyond this single driver. High-risk genomic profiles (HGP)-additional chromosomal abnormalities in Philadelphia-positive cells, Philadelphia chromosome-associated rearrangements, and high-risk somatic mutations detected by next-generation sequencing (NGS)-are present at diagnosis in roughly one-third of chronic-phase (CP) patients and shape response, progression, and survival. We propose a clinically actionable taxonomy of HGP based on biological origin, detection method, and TKI sensitivity. Central to it is ASXL1, the most consequential somatic variant in CML. ASXL1 mutations are present in 7-14% of newly diagnosed CP patients and independently predict inferior response, treatment failure, and ABL1 kinase domain mutations, even with potent frontline tyrosine kinase inhibitors (TKIs), including asciminib. By contrast, the adverse impact of Ph-associated rearrangements is overcome by potent TKIs. A newly described sixth pattern of mutation dynamics-de novo DTA (DNMT3A, TET2, ASXL1) mutations in 24% of optimal responders with a median doubling time of 68 days-supports serial NGS monitoring every 6-7 months as a noninvasive complement to cytogenetics. We present a practical decision framework across the key management nodes of CML: diagnosis, monitoring, treatment failure, and blast phase.